ABSTRACT Alzheimer's disease (AD) is an incurable neurodegenerative disorder that causes progressive memory loss and cognitive impairment, leaving patients totally incapacitated. The two landmark lesions in AD are extracellular amyloid plaques mainly formed by the amyloid beta-42 (Abeta) peptide and intracellular neurofibrillary tangles containing aggregates of abnormal tau protein. Abeta and tau were thought of as independent culprits for a long time, but in light of recent studies, it is clear that they are intimately related and have synergistic activities. Unfortunately, very little is known about how (and which) Abeta and tau interactions trigger AD pathogenesis, which significantly impedes the development of effective therapies. To address this, we have created a new fly model of AD that genetically produces both human Abeta and wild-type tau. Our preliminary data show that these ?humanized? flies display extracellular deposition of Abeta, intracellular aggregation of pathological tau, and robust neurodegeneration. The robust pathology of these flies provides an ideal platform to conduct a large-scale identification of genes that can suppress Abeta+tau neurotoxicity. Therefore, we will cross Abeta+tau flies with a next-generation library of 6,484 RNAi Drosophila strains to specifically silence human homologue genes. We will first perform a primary screen in the fly eye, which provides a fast visual result of the effect of silencing every gene (Aim 1). Then, we will validate the most potent suppressors for behavioral functions, preservation of brain neurons, and development of pathological markers (Aim 2). We anticipate that this experimental approach will uncover critical/novel targets for intervention not available to classical experimental models. Thus, the first large-scale attempt at discovering Abeta+tau suppressors will not only provide information about disease mechanisms but also identify relevant therapeutic targets to approach this overwhelming disorder. Of note, this project fits perfectly with the Strategy 1B of the National Plan to Address Alzheimer's Disease, which aims at expanding research on the molecular mechanisms and networks to enable the identification and selection of therapeutic targets.